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Activation of the Crtc2/Creb1 transcriptional network in skeletal muscle enhances weight loss during intermittent fasting

ABSTRACT: Exercise is a behavior modification indispensable for long-term weight loss. Exercise activates the Creb-Regulated Transcriptional Coactivator (Crtc) family of transcriptional coregulators to drive Creb1-mediated anabolic transcriptional programs in skeletal muscle. Here, we show that induced overexpression of a skeletal muscle specific Crtc2 transgene in aged mice leads to greater weight loss during alternate day fasting, and selective loss of fat rather than lean mass. Transcriptional profiling revealed that fasting and weight loss downregulated most of the mitochondrial electron transport genes and other regulators of mitochondrial function that were substantially reversed in the Crtc2 mice, which maintained higher energy expenditure during fasting. The Crtc2 mice displayed greater mitochondrial activity, metabolic flux capacity for both carbohydrates and fats, improved glucose tolerance and insulin sensitivity, and increased oxidative capacity before the fast, suggesting muscle-intrinsic mechanisms in support of improved weight loss. This work reveals that Crtc2/Creb1-mediated signaling coordinates metabolic adaptations in skeletal muscle that explain how Crtc2/Creb contribute to the effects of exercise on metabolism and weight loss.

ORGANISM(S): Mus musculus

PROVIDER: GSE149150 | GEO | 2021/11/09

REPOSITORIES: GEO

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Activation of the Crtc2/Creb1 transcriptional network in skeletal muscle enhances weight loss during intermittent fasting

Project description:Activation of the Crtc2/Creb1 transcriptional network in skeletal muscle enhances weight loss during intermittent fasting

| PRJNA627469 | ENA

Changes in Northern Elephant Seal Skeletal Muscle Following Thirty Days of Fasting and Reduced Activity

Project description:Northern elephant seals (NES, Mirounga angustirostris) undergo an annual molt during which they spend ~40 days fasting on land with reduced activity and lose approximately one-quarter of their body mass. Reduced activity and muscle load in stereotypic terrestrial mammalian models results in decreased muscle mass and capacity for force production and aerobic metabolism. However, the majority of lost mass in fasting female NES is from fat while muscle mass is largely preserved. Although muscle mass is preserved, potential changes to the metabolic and contractile capacity are unknown. To assess potential changes in NES skeletal muscle during molt, we collected muscle biopsies from 6 adult female NES at the beginning of the molt and after ~30 days at the end of the molt. Skeletal muscle was assessed for respiratory capacity using high resolution respirometry, and RNA was extracted to assess changes in gene expression. Despite a month of reduced activity, fasting, and weight loss, skeletal muscle respiratory capacity was preserved with no change in OXPHOS respiratory capacity. Molt was associated with 162 upregulated genes including genes favoring lipid metabolism and regulating cell cycles. We identified 172 downregulated genes including those coding for ribosomal proteins and genes associated with skeletal muscle force transduction and glucose metabolism. Following ~30 days of molt, NES skeletal muscle metabolic capacity appears largely preserved although mechanotransduction may be compromised. In the absence of exercise stimulus, fasting-induced shifts in skeletal muscle lipid metabolism may stimulate lipid signaling pathways associated with preserving the mass and metabolic capacity of slow oxidative muscle.

2020-09-15 | GSE151509 | GEO

microRNA expression during skeletal muscle differentiation and exercse in skeletal muscle.

Project description:To investigate microRNAs related to mitochondria biogenesis in skeletal muscle, microRNA expressions during skeletal muscle differentiation and exercise were analyzed in vivo and in vitro. Murine skeletal muscle cell (C2C12) were assigned to undifferentiated, differentiated, and passively stretched (exercise mimicked). C57BL/6S mice were assigned to resting, acute exercise (1day), and chronic exercise (7days). Low molecular weight RNA (< 200 nucleotides) was isolated from C2C12 cell or tibialis anterior muscle of mice and hybridized to Ncode microRNA microarrays. The experiment was performed using a loop design for the data analysis.

2011-05-14 | E-GEOD-29286 | biostudies-arrayexpress

Age-dependent impact of two exercise training regimens on genomic and metabolic remodeling in skeletal muscle and liver of male mice

Project description:How skeletal muscle adapts to different types of exercise intensity with age is not known. Adult and old C57BL/6 male mice were assigned to one of three groups: sedentary, daily high-intensity intermittent training (HIIT), or moderate intensity continuous training (MICT) for 4 weeks, compatible with the older group’s exercise capacity. Improvements in body composition, fasting blood glucose, and muscle strength were mostly observed in the MICT old group, while effects of HIIT training in adult and old animals was less clear. Skeletal muscle exhibited structural and functional adaptations to exercise training, as revealed by electron microscopy, OXPHOS assays, respirometry, and muscle protein biomarkers. Transcriptomics analysis of gastrocnemius muscle combined with liver and serum metabolomics unveiled an age-dependent metabolic remodeling in response to exercise training. These results support a tailored exercise prescription approach aimed at improving health and ameliorating age-associated loss of muscle strength and function in the elderly.

2022-07-06 | GSE175622 | GEO

Effects of Acute Aerobic Exercise on Skeletal Muscle Transcriptomics in Lean vs Overweight/Obese Men

Project description:Acute aerobic exercise has been shown to improve skeletal muscle mitochondrial function and completeness of fatty acid β-oxidation which contribute to improved insulin sensitivity. The effectiveness of acute exercise on improving mitochondrial adaptations, leading to improved insulin sensitivity, in overweight/obese (Ov/Ob) individuals is controversial. This study aimed to determine the effects of acute exercise on epigenetic regulation of genes involved in skeletal muscle mitochondrial adaptations in lean vs Ov/Ob men.

2017-12-30 | GSE108643 | GEO

Effects of Acute Aerobic Exercise on Whole Genome Nucleosome Maps in Skeletal Muscle of Lean vs Overweight/Obese Men

Project description:Acute aerobic exercise has been shown to improve skeletal muscle mitochondrial function and completeness of fatty acid β-oxidation which contribute to improved insulin sensitivity. The effectiveness of acute exercise on improving mitochondrial adaptations, leading to improved insulin sensitivity, in overweight/obese (Ov/Ob) individuals is controversial. This study aimed to determine the effects of acute exercise on epigenetic regulation, specifically nucleosome positioning, of genes involved in skeletal muscle mitochondrial adaptations in lean vs Ov/Ob men.

2017-12-30 | GSE108642 | GEO

Ketone flux through BDH1 supports metabolic remodeling of skeletal and cardiac muscles in response to intermittent time-restricted feeding

Project description:Time-restricted feeding (TRF) has gained attention as a dietary regimen that promotes metabolic health. This study sought to determine if ketone flux in skeletal and cardiac muscles plays an essential role in conferring the health benefits of an intermittent TRF (iTRF) schedule. Notably, we found that the ketolytic enzyme, beta-hydroxybutyrate dehydrogenase 1 (BDH1), is uniquely enriched in isolated mitochondria derived from heart and red/oxidative skeletal muscles, which also have high capacity for fatty acid oxidation (FAO). Using mice with muscle/heart-specific BDH1 deficiency, we discover that this enzyme is required for optimal FAO efficiency and exercise tolerance during acute fasting. Additionally, iTRF leads to robust molecular remodeling of muscle tissues and BDH1 flux is indeed required for the full adaptive benefits of this regimen, including increased lean mass, mitochondrial hormesis, and metabolic rerouting of pyruvate. In sum, ketone utilization enhances mitochondrial bioenergetics and supports iTRF-induced remodeling of skeletal muscle and heart.

2024-02-09 | PXD047114 | JPOST Repository

Metabolic regulation of BCAAs and glycogen via IRF4 in skeletal muscle

Project description:Skeletal muscle is not only a primary site for glucose uptake and storage, but also a reservoir for amino acids stored as protein. How the metabolism of these two fuels is coordinated in skeletal muscle is incompletely understood. Here, we demonstrate that interferon regulatory factor 4 (IRF4) integrate glucose and amino acids flux by regulating glycogen synthesis and branched-chain-amino acid (BCAA) metabolism in skeletal muscle. Mice with IRF4 specifically knocked out in skeletal muscle (MI4KO) showed elevated plasma BCAAs and skeletal muscle glycogen content, decreased adiposity and body weight, along with increased energy expenditure, remarkable improvements in glucose and insulin tolerance, and protection from diet-induced obesity (DIO). Loss of IRF4 caused downregulation of the mitochondrial branched-chain aminotransferase isozyme (BCATm) in myocytes, which encodes for the enzyme catalyzing the first step of BCAA metabolism. Lack of IRF4 also led to the upregulation of protein targeting to glycogen (PTG), which is associated with enhanced mitochondrial Complex II activity and mitochondria number. Additionally, overexpression of IRF4 in skeletal muscle caused obesity and reduced exercise capacity. Mechanistically, we found that IRF4 directly regulates both BCATm and PTG expression, and that overexpression of BCATm can partially reverse the effects of IRF4 deletion. These studies establish IRF4 as a novel driver of both glucose and BCAA metabolism in skeletal muscle.

2019-08-30 | GSE136623 | GEO

Short-term low calorie diet remodels skeletal muscle lipid profile and metabolic gene expression in obese adults

Project description:OBJECTIVE Diet intervention in obese adults is the first strategy to induce weight loss and to improve insulin sensitivity. We hypothesized that improvements in insulin sensitivity after weight loss from a short-term dietary intervention tracks with alterations in expression of metabolic genes and abundance of specific lipid species. RESEARCH DESIGN AND METHODS Eight obese, insulin resistant, non-diabetic adults were recruited to participate in a three-week low calorie diet intervention study (1000 kcal/day). Fasting blood samples and vastus lateralis skeletal muscle biopsies were obtained before and after the dietary intervention. Clinical chemistry and measures of insulin sensitivity were determined. Unbiased microarray gene expression and targeted lipidomic analysis of skeletal muscle was performed. RESULTS Body weight was reduced, insulin sensitivity (HOMA-IR) was enhanced, and serum insulin concentration and blood lipid (triglyceride, cholesterol, LDL and HDL) levels were improved after dietary intervention. Gene set enrichment analysis of skeletal muscle revealed that oxidative phosphorylation and inflammatory processes were among the most enriched KEGG-pathways identified after dietary intervention. mRNA expression of PDK4 and MLYCD increased, while SCD decreased in skeletal muscle after dietary intervention. Dietary intervention altered the intramuscular lipid profile of skeletal muscle, with changes in content of phosphatidylcholine and triglyceride species among the pronounced. CONCLUSIONS Short-term diet intervention and weight loss in obese adults alters metabolic gene expression and reduces specific phosphatidylcholine and triglyceride species in skeletal muscle, concomitant with improvements in clinical outcomes and enhanced insulin sensitivity.

2019-02-05 | GSE103682 | GEO

Exercise training markedly augments dietary weight loss-induced improvements in multi-organ system metabolic function in people with obesity and prediabetes

Project description:The additional therapeutic effects of regular exercise during a dietary weight loss program in people with obesity and prediabetes are unclear. We evaluated the effect of 10% weight loss, induced within ~5 months by calorie-restriction alone (Diet-ONLY, n=8) or calorie-restriction plus multi-modal exercise training (Diet+EX, n=8), on metabolic function in people with obesity and prediabetes. Whole-body (primarily muscle) and hepatic insulin sensitivity were 2-3 fold greater in the Diet+EX than the Diet-ONLY group, and were accompanied by increased muscle expression of genes involved in mitochondrial biogenesis, energy metabolism and angiogenesis in the Diet+EX group without any change in the Diet-ONLY group. There were no differences between groups in plasma branched-chain amino acids or markers of inflammation, and both interventions caused similar changes in the gut microbiome. These results demonstrate that adding regular exercise to a diet-induced weight loss program has profound metabolic benefits in people with obesity and prediabetes.

2023-04-26 | GSE230002 | GEO

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